A number of emerging or current therapies involve intravenous injection of small (less than 50 Kdaltons) protein, polypeptide or polysaccharide effectors. Such effectors can include Fab antibody fragments for use in active immunity, cytokines and cellular growth factors for stimulating immunological inflammatory responses, hormones, and polysaccharides, which are capable of interacting with endothelial cell receptors to competitively block neutrophil binding to activated endothelial cells lining the blood vessel (Katre, N. V., et al., Proc. Natl. Acad. Sci. USA 84:1487–1491 (1987); Philips, M. L., et al., Science 250:1130–1132 (1990); Waldmann, T. A., Annu. Rev. Immunol. 10:675–704 (1992)).
Other small polypeptide effectors have been proposed for use in blocking viral infection of target cells in the blood, such as a CD4+ glycopeptide which is effective to inhibit binding of human immunodeficiency virus (HIV) to CD4+ cells (Capon, D. J. and Ward, R. H. R., Ann. Rev. Immunol. 9:649–678 (1991); Janeway, C. A., Ann. Rev. Immunol. 10:645–674 (1992)).
Polymyxin B, a small basic peptide which is rapidly excreted by the kidneys, is known to react with and neutralize gram-negative bacterial endotoxins, specifically E. coli 0111:B4 liposaccharide (LPS) (Baldwin, G., et al., J. Infect. Diseas. 164:542–549 (1991)). It is not often administered parenterally as a treatment for septic shock syndrome, because high doses of polymyxin B are required for effective treatment. High doses can be fatal, due to renal toxicity, making advanced stages of septic shock difficult to treat.
The problem of rapid renal clearance observed with polymyxin B is also applicable to other small peptides, such as those discussed above, which have been used for parenteral treatment of disease. In general, circulating proteins which are smaller than about 50–60 Kdaltons will be cleared by the kidneys with a lifetime of less than 1–2 hours.
In some cases, peptide molecular weight can be increased above the threshold 50–60 Kdalton size by derivatizing the peptide with biologically compatible polymers, such as polyethyleneglycol (PEG) (e.g., U.S. Pat. No. 4,179,337). However, this strategy may not always be effective for small effectors, e.g., those with molecular weights less than about 5–10 Kdalton. Moreover, derivatizing a polypeptide with a plurality of PEG chains may destroy or reduce the polypeptide activity, and/or mask key activity sites of the polypeptide.